氟马替尼治疗慢性粒细胞白血病疗效及远期预后分析^*

Efficacy and Long-term Prognosis of Flumatinib in the Treatment of Chronic Myelocytic Leukemia

摘要

目的 采用倾向性评分匹配（PSM）均衡基线混杂因素，评估氟马替尼治疗慢性粒细胞白血病（CML）的临床疗效与安全性。方法 回顾性选取2019年1月-2025年1月195例CML患者作为研究对象，根据治疗方案分为伊马替尼组和氟马替尼组。通过PSM控制混杂因素，比较两种药物的早期治疗反应及长期生存结局〔总生存期（OS）〕，进一步分析患者远期预后。结果 PSM后共有61对患者完成匹配。氟马替尼一线治疗3个月时的完全血液学反应（CHR）、早期分子学缓解（EMR）率分别为96.72%、83.61%，其中EMR率高于伊马替尼治疗（P<0.001）；氟马替尼一线治疗6、9、12个月时的主要分子学反应（MMR）率分别为34.43%、50.82%、59.02%，一线治疗9、12个月时的深度分子学缓解（MR⁴）率分别为19.67%、27.87%，一线治疗3、6、12个月时的完全细胞遗传学缓解（CCyR）率分别为67.21%、85.25%、91.80%，均高于伊马替尼治疗（P<0.05）。广义估计方程分析显示，氟马替尼组的MMR达标概率高于伊马替尼组〔Waldχ²=16.280，P<0.001，比值比（OR）=2.130，95%置信区间（CI）：1.570～2.890〕；时间效应提示两组MMR达标概率均随治疗时间延长升高（Waldχ²=48.720，P<0.001）；组×时间交互效应具有统计学意义（Waldχ²=8.940，P=0.003）。氟马替尼组患者治疗期间腹泻发生率最高（26.23%），伊马替尼组患者血小板减少症发生率最高（31.15%）。此外，伊马替尼组皮疹、水肿发生率较氟马替尼组高（P<0.05）；其他不良反应发生率差异无统计学意义（P>0.05）。中位随访时长为43（37，52）个月。截至随访终止时，共7例患者死亡，其中伊马替尼组4例，死亡率6.56%（4/61），氟马替尼组3例，死亡率4.92%（3/61），两组患者OS比较差异无统计学意义（log-rankP=0.955）。结论 氟马替尼相较于伊马替尼治疗CML，具有更好的短期疗效和安全性。尽管长期OS无显著改善，氟马替尼仍可以作为CML的有效一线治疗。

Abstract

Objective To evaluate the clinical efficacy and safety of flumatinib in the treatment of chronic myelocytic leukemia (CML) by using propensity score matching (PSM) to balance baseline confounding factors. Methods A retrospective cohort of 195 patients with CML treated between January 2019 and January 2025 was selected for this study. Patients were stratified into imatinib and flumatinib groups based on their treatment regimens. PSM was employed to control for confounding variables, enabling a comparative analysis of early treatment responses and long-term survival outcomes, including overall survival (OS), between the two tyrosine kinase inhibitor therapies, as well as further analysis of long-term prognosis. Results Through PSM, a total of 61 patient pairs were successfully matched. In the flumatinib group, the rates of complete hematologic response (CHR) and early molecular response (EMR) at 3 months of first-line treatment were 96.72% and 83.61%, respectively, with the EMR rate being significantly higher than achieved with imatinib treatment (P < 0.001). For flumatinib, the rates of cumulative major molecular response (MMR) at 6, 9, and 12 months of first-line therapy were 34.43%, 50.82%, and 59.02%, respectively, all exceeding those observed with imatinib ( P < 0.05). The molecular response 4 (MR ⁴) rates for flumatinib at 9 and 12 months of first-line treatment were 19.67% and 27.87%, respectively, also higher than those for imatinib (P < 0.05). Additionally, the cumulative complete cytogenetic response (CCyR) rates for flumatinib at 3, 6, and 12 months of first-line treatment were 67.21%, 85.25%, and 91.28%, respectively, consistently outperforming imatinib ( P < 0.05). Generalized estimating equation analysis revealed that patients in the flumatinib group had a significantly higher probability of achieving MMR than those in the imatinib group (Wald χ² = 16.280, P < 0.001, odds ratio [OR] = 2.130, 95% CI: 1.570-2.890). The time effect indicated that the probability of achieving MMR increased with the extension of treatment duration in both groups (Wald χ² = 48.720, P < 0.001). In addition, a statistically significant group-by-time interaction effect was observed (Wald χ² = 8.940, P = 0.003). During the treatment period, the highest incidence of diarrhea was observed in the flumatinib group (26.23%), while thrombocytopenia was most prevalent in the imatinib group (31.15%). Furthermore, the imatinib group exhibited higher incidences of rash and edema compared to the flumatinib group (P < 0.05). No significant differences were observed in the incidence of other adverse events between the groups ( P > 0.05). The median follow-up duration was 43 (37, 52) months. By the end of the follow-up, a total of 7 patients had died, with 4 deaths (6.56% [4/61]) in the imatinib group and 3 deaths (4.92% [3/61]) in the flumatinib group. The comparison of OS between the two groups revealed no statistically significant difference (log-rank P = 0.955). Conclusion Compared with imatinib, flumatinib demonstrates superior short-term efficacy and safety profile in the treatment of CML. Despite the lack of significant improvement in long-term OS, flumatinib can still serve as an effective first-line therapeutic option for patients with CML.

关键词

慢性粒细胞白血病 / 氟马替尼 / 伊马替尼 / 倾向性评分

Key words

Chronic myelocytic leukemia / Flumatinib / Imatinib / Propensity score matching

参考文献

[1] Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring[J]. Am J Hematol, 2024, 99(11): 2192. DOI: 10.1002/ajh.27443.

[2] Elmakaty I, Saglio G, Al-khabori M, et al. The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings[J/OL]? Cancers, 2024, 16(4): 754. https://doi.org/10.3390/cancers16040754.

[3] Mojtahedi H, Yazdanpanah N, Rezaei N. Chronic myeloid leukemia stem cells: targeting therapeutic implications[J/OL]. Stem Cell Res Ther, 2021, 12(1): 603. https://pmc.ncbi.nlm.nih.gov/articles/PMC8684082/. DOI: 10.1186/s13287-021-02659-1.

[4] Wang Y, Liang Z J, Gale R P, et al. Chronic myeloid leukaemia: Biology and therapy[J/OL]. Blood Rev, 2024, 65: 101196. https://doi.org/10.1016/j.blre.2024.101196.

[5] Wang W, Sun Q. Novel targeted drugs approved by the NMPA and FDA in 2019[J/OL]. Signal Transduct Target Ther, 2020, 5(1): 65. https://pmc.ncbi.nlm.nih.gov/articles/PMC7205905/. DOI: 10.1038/s41392-020-0164-4.

[6] Dai H, Wang J, Huang Z, et al. LncRNA OIP5-AS1 Promotes the Autophagy-Related Imatinib Resistance in Chronic Myeloid Leukemia Cells by Regulating miR-30e-5p/ATG12 Axis[J/OL]. Technol Cancer Res Treat, 2021, 20: 15330338211052150. https://pmc.ncbi.nlm.nih.gov/articles/PMC8564130/. DOI: 10.1177/15330338211052150.

[7] 中华医学会血液学分会. 慢性髓细胞性白血病中国诊断与治疗指南 (2025年版)[J]. 中华血液学杂志, 2025, 46(12): 1082. DOI:10.3760/cma.j.cn121090-20250923-00437.

[8] Chinese Society of Hematology. Guideline for the diagnosis and treatment of chronic myeloid leukemia in China (2025)[J]. Chin J Hematol, 2025, 46(12): 1082. DOI:10.3760/cma.j.cn121090-20250923-00437.

[9] 中华医学会血液学分会. 慢性髓性白血病中国诊断与治疗指南(2020年版)[J]. 中华血液学杂志, 2020, 41(5): 357. DOI: 10.3760/cma.j.issn.0253-2727.2020.05.001.

[10] Hematology Branch of Chinese Medical Association. The guidelines for diagnosis and treatment of chronic myelogenous leukemia in China (2020 edition)[J]. Chin J Hematol, 2020, 41(5): 357. DOI:10.3760/cma.j.issn.0253-2727.2020.05.001.

[11] Micu M L, Cira S F, Zdrenghea M, et al. In-depth analysis for TKI-driven real-world management of 201 CML patients using TFR[J/OL]. Front Pharmacol, 2025, 16: 1673056. https://doi.org/10.3389/fphar.2025.1673056.

[12] Zhang J J, Qian Y L, Wu Z Y, et al. Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis[J]. Transl Cancer Res, 2024, 13(7): 3791. DOI: 10.21037/tcr-24-747.

[13] Zhang L, Meng L, Liu B, et al. Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase Ⅲ, Randomized, Open-label, Multi-center FESTnd Study[J]. Clin Cancer Res, 2021, 27(1): 73. DOI: 10.1158/1078-0432.CCR-20-1600.

[14] Baty R S. Protective effect of Bosutinib with caspase inhibitors on human K562 cells[J]. Saudi J Biol Sci, 2022, 29(4): 2327. DOI: 10.1016/j.sjbs.2021.11.068.

[15] Rodriguez J, Iniguez A, Jena N, et al. Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy[J/OL]. eLife, 2023, 12: e84149. https://doi.org/10.7554/eLife.84149.

[16] Sayın S, Yıldırım M, Erdoğdu B, et al. Metabolomic Profiling and Bioanalysis of Chronic Myeloid Leukemia: Identifying Biomarkers for Treatment Response and Disease Monitoring[J/OL]. Metabolites, 2025, 15(6): 376. https://doi.org/10.3390/metabo15060376.

[17] Zenebe B, Nigussie H, Belay G, et al. A review on characterization of BCR-ABL transcript variants for molecular monitoring of chronic myeloid leukemia phenotypes[J/OL]. Hematology, 2023, 28(1): 2284038. https://doi.org/10.1080/16078454.2023.2284038.

[18] Mohanavelu P, Mutnick M, Mehra N, et al. Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia[J/OL]. Cancers, 2021, 13(7): 1643. https://doi.org/10.3390/cancers13071643.

[19] Kronick O, Chen X, Mehra N, et al. Hematological Adverse Events with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Systematic Review with Meta-Analysis[J/OL]. Cancers (Basel), 2023, 15(17): 4354. https://doi.org/10.3390/cancers15174354.

[20] Lei Y, Zhao X, Qiao C, et al. Real-world comparison of flumatinib and nilotinib as first-line therapy for patients with chronic phase chronic myeloid leukemia: a multicenter retrospective study[J/OL]. Ther Adv Med Oncol, 2025, 17: 17588359251335905. https://pmc.ncbi.nlm.nih.gov/articles/PMC12041721/. DOI: 10.1177/17588359251335905.

[21] Yoshifuji K, Sasaki K. Adverse events and dose modifications of tyrosine kinase inhibitors in chronic myelogenous leukemia[J/OL]. Front Oncol, 2022, 12: 1021662. https://doi.org/10.3389/fonc.2022.1021662.

[22] Hochhaus A, Baccarani M, Silver R T, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia[J]. Leukemia, 2020, 34(4): 976. DOI: 10.1038/s41375-020-0776-2.

[23] Xu L, Tu G, Cai Z, et al. Predicting in-hospital mortality in ICU patients with lymphoma using machine learning models[J/OL]. PLoS One, 2025, 20(8): e0330197. https://doi.org/10.1371/journal.pone.0330197.

[24] Bauer S, Comer H, Ramsey B, et al. Management of Adverse Events Associated With Tyrosine Kinase Inhibitor Use in Adult Patients With Chronic Myeloid Leukemia in Chronic Phase: An Advanced Practice Perspective[J]. J Adv Pract Oncol, 2021, 12(5): 521. DOI: 10.6004/jadpro.2021.12.5.7.

[25] 王珂, 尹列芬, 杨欢, 等. 酪氨酸激酶抑制剂治疗慢性粒细胞白血病的不良反应及处理的研究进展[J]. 实用药物与临床, 2022, 25(1): 89-90. DOI: 10.14053/j.cnki.ppcr.202201017.

[26] Wang K, Yin L F, Yang H, et al. Adverse events of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia and the management[J]. Pract Pharm Clin Rem, 2022, 25(1): 89-90. DOI: 10.14053/j.cnki.ppcr.202201017.

[27] Boucher L, Sorel N, Desterke C, et al. Deciphering Potential Molecular Signatures to Differentiate Acute Myeloid Leukemia (AML) with BCR:ABL1 from Chronic Myeloid Leukemia (CML) in Blast Crisis[J/OL]. Int J Mol Sci, 2023, 24(20): 15441. https://doi.org/10.3390/ijms242015441.

[28] 张春燕, 辛晓丽, 苏小丽, 等. CML慢性期伴附加染色体异常患者TKI疗效分析[J]. 兰州大学学报(医学版), 2022, 48(12): 45. DOI: 10.13885/j.issn.1000-2812.2022.12.008.

[29] Zhang C Y, Xin X L, Su X L, et al. TKI efficacy in CML patients with additional chromosomal abnormality[J]. J Lanzhou Univ (Med Sci), 2022, 48(12): 45. DOI: 10.13885/j.issn.1000-2812.2022.12.008.

基金资助

*2023年度安徽省高校自然科学研究项目(2023AH053319)